[7-(3-disubstituted amino)phenyl]pyrazolo[1,5-a]pyrimidines

ABSTRACT

Novel [7-(3-disubstituted amino)phenyl]pyrazolo[1,5-a]pyrimidines useful as anxiolytic, antiepileptic and sedative-hypnotic agents as well as skeletal muscle relaxants, methods of using these compounds, compositions of matter containing them and processes for their production.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part of our copending application,U.S. application Ser. No. 612,812, filed May 24, 1984, now U.S. Pat. No.4,521,422, which is a continuation-in-part of U.S. application Ser. No.506,966, filed June 23, 1983, now abandoned.

SUMMARY OF THE INVENTION

This invention relates to new organic compounds which are[7-(3-disubstituted amino)phenyl]pyrazolo[1,5-a]pyrimidines, which areuseful as anxiolytic and antiepileptic agents as well assedative-hypnotic agents and skeletal muscle relaxants. This inventionalso relates to the methods of using the novel compounds, tocompositions of matter containing them as the active ingredient and toprocesses for their production.

DETAILED DESCRIPTION OF THE INVENTION

The novel compounds of this invention are represented by the followingstructural formula: ##STR1## wherein R₁ is selected from the groupconsisting of: hydrogen, halogen, cyano and ##STR2## R2 is selected fromthe group consisting of hydrogen and alkyl(C₁ -C₃); R₃ is ##STR3## R₄ isselected from the group consisting of hydrogen, alkyl(C₁ -C₆) andalkoxy(C₁ -C₆); R₅ is selected from the group consisting of hydrogen,alkyl(C₁ -C₆), alkenyl(C₂ -C₆), --CH₂ C.tbd.CH, cycloalkyl(C₃-C₆)methyl, --CH₂ OCH₃ and --CH₂ CH₂ OCH_(3;) and R₆ is selected fromthe group consisting of alkyl(C₁ -C₆), cycloalkyl(C₃ -C₆), --O--alkyl(C₁-C₆), --NH--alkyl(C₁ -C₃), --N--dialkyl(C₁ -C₃), --(CH₂)_(n)--O--alkyl(C₁ -C₃), --(CH₂)_(n) --NH-alkyl(C₁ --C₃) and--(CH₂)n--N--dialkyl(C₁ -C₃), where n is an integer 1 to 3 inclusive.

The most preferred compounds of this invention are the compounds of theabove formula wherein R₁ is cyano or ##STR4## R₂ is hydrogen; R₄ isalkyl(C₁ -C₆); R₅ is alkyl(C₁ -C₆), alkenyl(C₂ -C₆) or --CH₂ .tbd.CH;and R₆ is alkyl(C₁ -C₆), cycloalkyl(C₃ -C₆) or --O --alkyl(C₁ -C₆).

The instant invention is additionally concerned with the methods whichemploy the above-described compounds in mammals to treat anxiety orepilepsy and to induce a sedative-hypnotic effect or relax skeletalmuscles, with compositions of matter containing the above-describedcompounds and with processes for producing the compounds.

The novel compounds of this invention may be readily prepared as setforth in the following reaction scheme: ##STR5##

In accordance with the above reaction scheme a 1-acetylphenyl-3-amide(1), where R6 is as described above is reacted with dimethylformamidedimethylacetal at reflux giving anN-[3-[3-(dimethylamino)-1-oxo-2-propenyl[phenyl]alkanamide, which isthen reacted with sodium hydride, and the anion generated is reactedwith an alkyl halide, where R₅ is as described, above giving theN-[3-[3-(dimethylamino)-1-oxo-2-propenyl]phenyl]-N-alkylalkanamide (2).This compound is than reacted with a 3-aminopyrazole (3), where R₁ andR₂ are as described above, in glacial acetic acid at reflux, giving theproduct (4).

Alternatively, N-[3-[3-(dialkylamino)-1-oxo-2-propenyl]phenyl]alkanamide(5) is reacted with a 3-aminopyrazole (3) to give intermediates (6)which are reacted with a base such as sodium hydride, sodium alkoxideand the like and an R₅ -halide to give the products (4). ##STR6##Details of the preparative scheme are fully apparent from the U.S. Pat.No. 4,521,422, which is hereby incorporated by reference.

The performance of the novel compounds of the present invention instandard tests with laboratory animals which are known to correlate wellwith relief of anxiety in man indicates that they possess centralnervous system activity at nontoxic doses and thus are useful asanxiolytic agents. Furthermore, these compounds have been shown bybiological data to be useful as antiepileptic agents, particularly inthe treatment of grand mal epilepsy seizures, and as sedative-hypnoticand skeletal muscle relaxant agents.

The anti-anxiety and anticonvulsant properties of the novel compounds ofthe present invention have been established in a test which indicatesanxiolytic and antiepileptic activity by the measure of protection theyprovide from convulsions resulting from the administration ofpentylenetetrazole. Single or graded dose levels of the test compoundswere administered orally or intraperitoneally in a 2% starch vehicle,containing 0.5% v/v polyethylene glycol and one drop of Polysorbate 80to groups of at least 4 rats. At 30 or 60 minutes, the rats were treatedintravenously with pentylenetetrazole at a dose of 23 mg/kg of bodyweight. This dose is estimated to cause clonic seizures in 99% ofunprotected rats. It has been reported [R. T. Hill and D. H. Tedeschi,"Animal Testing and Screening Procedures in Evaluating PsychotropicDrugs" in "An Introduction to Psychopharmacology", Eds. R. R. Rech andK. E. Moore, Raven Press, New York, p. 237-288 (1971)] that there is ahigh degree of correlation between the ability of compounds to inhibitthe seizure-inducing effect of pentylenetetrazole in rats and theeffectiveness of those compounds as anxiolytic and anticonvulsive agentsin higher warm-blooded animals. The results of this test onrepresentative compounds of the present invention are shown in Table I.

                  TABLE I                                                         ______________________________________                                        Protection Against Clonic Seizures Caused by                                  Pentylenetetrazole in Rats                                                                          Dose     % of Rats                                      Compound              (mg/kg)  Protected                                      ______________________________________                                         .sub.--N--[3-(3-cyanopyrazolo[1,5- -a]pyrimidin-                                                   25.0     100                                            7-yl)phenyl]- .sub.--N--ethylpropanamide                                       .sub.--N--[3-(3-cyanopyrazolo[1,5- -a]pyrimidin-                                                   25.0     100                                            7-yl)phenyl]- .sub.--N--ethylacetamide                                         .sub.--N--[3-(3-chloropyrazolo[1,5- -a]pyrimi-                                                     25.0     100                                            din-7-yl)phenyl]- .sub.--N--ethylacetamide                                     .sub.--N--[3-(3-cyanopyrazolo[1,5- -a]pyrimidin-                                                   6.25     100                                            7-yl)phenyl]- .sub.--N--propylacetamide                                       [3-(3-cyanopyrazolo[1,5- -a]pyrimidin-7-                                                            3.1      25                                             yl)phenyl]methylcarbamic acid, methyl                                         ester                                                                         [3-(3-cyanopyrazolo[1,5- -a]pyrimidin-7-                                                            12.6     75                                             yl)phenyl]ethylcarbamic acid, methyl                                          ester                                                                          .sub.--N--butyl- .sub.--N--[3-(3-cyanopyrazolo[1,5- -a]-                                           25.0     50                                             pyrimidin-7-yl)phenyl]acetamide                                               [3-(3-cyanopyrazolo[1,5- -a]pyrimidin-7-                                                            25.0     25                                             yl)phenyl]ethylcarbamic acid, ethyl                                           ester                                                                         [3-(3-chloropyrazolo[ 1,5- -a]pyrimidin-                                                            25.0     25                                             7-yl)phenyl]ethylcarbamic acid, ethyl                                         ester                                                                          .sub.--N--[3-(3-cyanopyrazolo[1,5- -a]pyrimidin-                                                   25.0     100                                            7-yl)phenyl]- .sub.--N--2-propenylacetamide                                    .sub.--N--[3-(3-cyanopyrazolo[1,5- -a]pyrimidin-                                                   6.25     100                                            7-yl)phenyl]- .sub.--N--2-propynylacetamide                                    .sub.--N--[3-(3-cyanopyrazolo[1,5- -a]pyrimidin-                                                   25.0     50                                             7-yl)phenyl]- .sub.--N--methylcyclobutanecar-                                 boxamide                                                                       .sub.--N--[3-(3-cyanopyrazolo[1,5- -a]pyrimidin-                                                   25.0     75                                             7-yl)phenyl]- .sub.--N--methylcyclopropanecar-                                boxamide                                                                       .sub.--N--[3-(3-cyanopyrazolo[1,5- -a]pyrimidin-                                                   25.0     75                                             7-yl)phenyl]- .sub.--N--methylacetamide                                        .sub.--N--[3-(3-cyanopyrazolo[1,5- -a]pyrimi-                                                      12.5     50                                             din-7-yl)phenyl]- .sub.--N--methylacetamide                                   7-[3-(acetylmethylamino)phenyl]pyra-                                                                25.0     100                                            zolo[1,5- -a]pyrimidine-3-carboxylic                                          acid, ethyl ester                                                              .sub.--N--[3-(3-cyanopyrazolo[1,5- -a]pyrimidin-                                                   12.5     50                                             7-yl)phenyl]- .sub.--N-- methylpropanamide                                     .sub.--N--[3-(3-cyano-2-methylpyrazolo[1,5- -a]-                                                   25.0     100                                            pyrimidin-7-yl)phenyl]- .sub.--N--methylpro-                                  panamide                                                                      ______________________________________                                    

Another test which has been used to assess antianxiety effects is anonconditioned passive avoidance procedure described by J. R. Vogel, B.Beer and D. E. Clody, "A Simple and Reliable Conflict Procedure forTesting Anti-Anxiety Agents", Psychopharmacologia, 21, 1-7 (1971). Aconflict situation is induced in rats by a modification of this method.

Groups of 6 native, Wistar strain rats, weighing 200-240 g each weredeprived of water for 48 hours and food for 24 hours. The test compoundswere administered in single or graded, oral or intraperitoneal doses,suspended in a 2% starch vehicle containing 0.5% v/v polyethylene glycoland one drop of polysorbate 80. Control animals received the vehiclealone. At 30 to 60 minutes each rat was placed in an individualplexiglass chamber. Water was available ad libitum from a tap located inthe rear of the chamber. A 0.7 milliampere DC shocking current wasestablished between the stainless steel grid floor and the tap. After 20licks of non-shocked drinking, a shock was delivered for 2 seconds andthen further shocks were delivered on a ratio of one shock for 2 secondsfor every 20 licks. This was continued for a total of 3 minutes. Thenumber of shocks taken by each rat during the 3 minute interval wasrecorded and compared to a control group. The test compounds areconsidered active if the number of shocks received by the test group issignificantly higher than the control group by the Mann-Witney U test.Results of this test on representative compounds of this inventionappear in Table II.

                  TABLE II                                                        ______________________________________                                        Nonconditioned Passive Avoidance Test in Rats                                                       Dose                                                    Compound              (mg/kg)  Result                                         ______________________________________                                         .sub.--N--3-(3-cyanopyrazolo[1,5- -a]pyrimidin-                                                    0.4      Active                                         7-yl)phenyl]- .sub.--N--ethylpropanamide                                       .sub.--N--3-(3-cyanopyrazolo[1,5- -a]pyrimidin-                                                    0.8      Active                                         7-yl)phenyl] .sub.--N--ethylacetamide                                          .sub.--N--ethyl- .sub.--N--(3-pyrazolo[1,5- -a]pyrimidin-                                          25.0     Active                                         7-ylphenyl)acetamide                                                           .sub.--N--[3-(3-chloropyrazolo[1,5- -a]pyrimi-                                                     3.1      Active                                         din-7-yl)phenyl]- .sub.--N--ethylacetamide                                     .sub.--N--[3-(3-cyanopyrazolo[1,5- -a]pyrimidin-                                                   1.5      Active                                         7-yl)phenyl]- .sub.--N--propylacetamide                                       [3-(3-cyanopyrazolo[1,5- -a]pyrimidin-7-                                                            3.1      Active                                         yl)phenyl]methylcarbamic acid, methyl                                         ester                                                                         [3-(3-cyanopyrazolo[1,5- -a]pyrimidin-7-                                                            12.5     Active                                         yl)phenyl]ethylcarbamic acid, methyl                                          ester                                                                         [3-(3-chloropyrazolo[1,5- -a]pyrimidin-                                                             25.0     Active                                         7-yl)phenyl]ethylcarbamic acid, ethyl                                         ester                                                                          .sub.--N--[3-(3-cyanopyrazolo[1,5- -a]pyrimidin-                                                   3.1      Active                                         7-yl)phenyl]- .sub.--N--2-propenylacetamide                                    .sub.--N--[3-(3-cyanopyrazolo[1,5- -a]pyrimidin-                                                   1.5      Active                                         7-yl)phenyl]- .sub.--N--2-propynylacetamide                                    .sub.--N--[3-(3-cyanopyrazolo[1,5- -a]pyrimidin-                                                   6.2      Active                                         7-yl)phenyl]- .sub.--N--methylpropaneamide                                     .sub.--N--[3-(3-cyano-2-methylpyrazolo[1,5- -a]-                                                   25.0     Active                                         pyrimidin-7-yl)phenyl]- .sub.--N--methylpropan-                               amide                                                                         7-[3-(acetylmethylamino)phenyl]pyra-                                                                25.0     Active                                         zolo[1,5- -a]pyrimidine-3-carboxylic                                          acid, ethyl ester                                                              .sub.--N--[3-(3-cyanopyrazolo[1,5- -a]pyrimidin-                                                   1.5      Active                                         7-yl)phenyl]- .sub.--N--methylacetamide                                        .sub.--N--[3-(3-chloropyrazolo[1,5- -a]pyrimi-                                                     3.1      Active                                         din-7-yl)phenyl]- .sub.--N--methylacetamide                                    .sub.--N--[3-(3-cyanopyrazolo[1,5- -a]pyrimidin-                                                   25.0     Active                                         7-yl)phenyl]- .sub.--N--methylcyclobutanecar-                                 boxamide                                                                      ______________________________________                                    

Another test utilized for the determination of anxiolytic activity isthe measurement of the ability of test compounds to inhibit the bindingof tritiated benzodiazepines to brain-specific receptors of warm-bloodedanimals. A modification of the method described by R. F. Squires, etal., Nature, 266, No. 21, p. 732 (April 1977) and H. Mohler, et al.,Science, 198, p. 849 (1977) was employed.

Male albino rats (Wistar strain, weighing 150-200 g each) were obtainedfrom Royalhart Farms. ³ H-Methyldiazepam (79.9 Ci/mmol) and ³H-methylflunitrazepam (84.3 Ci/mmol) were obtained from New EnglandNuclear. The test compounds were solubilized in eitherdimethylformamide, acetic acid, ethanol or hydrochloric acid.

Whole cortex of rats was homogenized gently in 20 volumes of ice-cold0.32 M sucrose, centrifuged twice at 1000 g for 10 minutes and thenrecentrifuged at 30,000 g for 20 minutes to produce a crude P₂-synaptosomal fraction. The P₂ -fraction was either: (1) resuspended intwice the original volume in hypotonic 50 mM Tris.HCl (pH 7.4), or (2)resuspended in one-half the original volume in hypotonic 10 mM Tris.HCl(pH 7.4) and then was frozen (-20° C.) until time of use. Frozen P₂preparations were thawed and resuspended in four times the originalhomogenizing volume at time of assay.

The binding assay consisted of 300 μl of the P₂ -fraction suspension(0.2-0.4 mg protein), 100 μl of test drug and 100 μl of ³ H-diazepam(1.5 nM, final concentration) or ³ H-flunitrazepam (1.0 nM, finalconcentration) which was added to 1.5 ml of 50 mM Tris.HCl (pH 7.4).Non-specific binding controls and total binding controls received 100 μlof diazepam (3 M, final concentration) and 100 μl of deionized water,respectively, in place of the test compound. Incubation for 30 minutesproceeded in ice and was terminated by filtration, under vacuum, throughWhatman GF/C glass fiber filters. The filters were washed twice with 5ml of ice-cold 50 mM Tris.HCl (pH 7.4) and placed in scintillationvials. After drying at 50°-60° C. for 30 minutes, 10 ml of BeckmanReady-Solv™ HP (a high performance pre-mix scintillation cocktail,registered trademark of Beckman Instruments, Inc., Irvine, CA 92713 )was added and the radioactivity determined in a scintillation counter.

Inhibition of binding was calculated by the difference between totalbinding and binding in the presence of test compound, divided by thetotal binding×100.

The results of this test on representative compounds of the presentinvention are given in Table III.

                  TABLE III                                                       ______________________________________                                        Inhibition of the Binding of .sup.3 H--Benzodiazepine                         to Brain-Specific Receptors of Rats                                           Compound                % Inhibition                                          ______________________________________                                         .sub.--N--[3-(3-cyanopyrazolo[1,5- -a]pyrimidin-7-                                                   83                                                    yl)phenyl]- .sub.--N--ethylpropanamide                                         .sub.--N--[3-(3-cyanopyrazolo[1,5- -a]pyrimidin-7-                                                   79                                                    yl)phenyl]- .sub.--N--ethylacetamide                                           .sub.--N--[3-(3-chloropyrazolo[1,5- -a]pyrimidin-7-                                                  97                                                    yl)phenyl]- .sub.--N--ethylacetamide                                           .sub.--N--[3-(3-cyanopyrazolo[1,5- -a]pyrimidin-7-                                                   64                                                    yl)phenyl]- .sub.--N--propylacetamide                                         7-[3-[ethyl(1-oxopropyl)amino]phenyl]pyra-                                                            100                                                   zolo[1,5- -a]pyrimidine-3-carboxylic acid,                                    ethyl ester                                                                   [3-(3-cyanopyrazolo[1,5- -a]pyrimidin-7-yl)-                                                          87                                                    phenyl]methylcarbamic acid, methyl ester                                      7-[3-[(methoxycarbonyl)methylamino]phenyl]-                                                           98                                                    pyrazolo[1,5- -a]pyrimidine-3-carboxylic                                      acid, ethyl ester                                                             [3-(3-cyanopyrazolo[1,5- -a]pyrimidin-7-yl)-                                                          55                                                    phenyl]ethylcarbamic acid, methyl ester                                       7-[3-[ethyl(methoxycarbonyl)amino]phenyl]-                                                            99                                                    pyrazolo[1,5- -a]pyrimidine-3-carboxylic                                      acid, ethyl ester                                                             [3-(3-cyanopyrazolo[1,5-  -a]pyrimidin-7-yl)-                                                         41                                                    phenyl]methylcarbamic acid, methyl ester                                      ethyl(3-pyrazolo[1,5- -a]pyrimidin-7-yl-                                                              61                                                    phenyl)carbamic acid, ethyl ester                                             [3-(3-cyanopyrazolo[1,5- -a]pyrimidin-7-yl)-                                                          63                                                    phenyl]ethylcarbamic acid, ethyl ester                                        [3-(3-chloropyrazolo[1,5- -a]pyrimidin-7-yl)-                                                         78                                                    phenyl]ethylcarbamic acid, ethyl ester                                         .sub.--N--[3-(3-cyanopyrazolo[1,5- -a]pyrimidin-7-                                                   78                                                    yl)phenyl]- .sub.--N--2-propenylacetamide                                      .sub.--N--[3-(3-cyanopyrazolo[1,5- -a]pyrimidin-7-                                                   91                                                    yl)phenyl]- .sub.--N--2-propynylacetamide                                      .sub.--N--[3-(3-cyano-2-methylpyrazolo[1,5- -a]                                                      42                                                    pyrimidin-7-yl)phenyl]propanamide                                              .sub.--N--[3-(3-cyanopyrazolo[1,5- -a]pyrimidin-7-                                                   79                                                    yl)phenyl]- .sub.--N--methylpropanamide                                        .sub.--N--[3-(3-cyano-2-methylpyrazolo[1,5- -a]-                                                     95                                                    pyrimidin-7-yl)phenyl]- .sub.--N--methylpropanamide                            .sub.--N--methyl- .sub.--N--(3-pyrazolo[1,5- -a]pyrimidin-7-                                         54                                                    ylphenyl)acetamide                                                            7-[3-(acetylmethylamino)phenyl]pyrazolo-                                                              100                                                   [1,5- -a]pyrimidine-3-carboxylic acid,                                        ethyl ester                                                                    .sub.-- N--[3-(3-cyanopyrazolo[1,5- -a]pyrimidin-7-                                                  73                                                    yl)phenyl]- .sub.--N--methylacetamide                                          .sub.--N--[3-(3-chloropyrazolo[1,5- -a]pyrimidin-7-                                                  71                                                    yl)phenyl]- .sub.--N--methylacetamide                                          .sub.--N--[3-(3-cyanopyrazolo[1,5- -a]pyrimidin-7-                                                   81                                                    yl)phenyl[- .sub.--N--methylcyclobutanecarboxiamde                             .sub.--N--[3-(3-cyanopyrazolo[1,5- -a]pyrimidin-7-                                                   83                                                    yl)phenyl]- .sub.--N--methylcyclopropanecarboxamide                           7-[3-[(cyclopropylcarbonyl)methylamino]-                                                              95                                                    phenylpyrazolo[1,5- -a]pyrimidine-3-car-                                      boxylic acid, ethyl ester                                                     7-[3-(acetylethylamino)phenyl]pyrazolo-                                                               97                                                    [1,5- -a]pyrimidine-3-carboxylic acid,                                        ethyl ester                                                                   7-[3-(acetylamino)phenyl]pyrazolo[1,5- -a]-                                                           85                                                    pyrimidine-3-carboxylic acid, ethyl ester                                     7-[3-[(methoxycarbonyl)amino]phenyl]-                                                                 76                                                    pyrazolo[1,5- -a]pyrimidine-3-carboxylic                                      acid, ethyl ester                                                             methyl(3-pyrazolo[1,5- -a]pyrimidin-7-yl-                                                             45                                                    phenyl)carbamic acid, methyl ester                                            7-[3-(acetylpropylamino)phenyl]pyrazolo-                                                              97                                                    [1,5- -a]pyrimidine-3-carboxylic acid,                                        ethyl ester                                                                   [3-(3-chloropyrazolo[1,5- -a]pyrimidin-7-                                                             92                                                    yl)phenyl]methylcarbamic acid, methyl ester                                   7-[3-[(cyclobutylcarbonyl)amino]phenyl]-                                                              82                                                    pyrazolo[1,5- -a]pyrimidine-3-carboxylic                                      acid, ethyl ester                                                             ______________________________________                                    

The novel compounds of this invention have also been shown to haveskeletal muscle relaxant activity through the use of two tests. Thefirst test measures the effect of representative compounds on theability of rats to remain on an inclined screen. Groups of at least 6rats were treated orally with graded doses of test compounds or vehicleand placed on a wire mesh screen (inclined at an angle of 60° from ahorizontal level) 65 minutes later. The number of rats falling off thescreen within 30 minutes was recorded. The ED₅₀ (dose necessary to cause50% of the animals tested to fall off) was calculated according to thelinear arcsine transformation method of Finney, D. J., "StatisticalMethods in Biological Assay", 2nd Ed., Hafner, N.Y., 1964, p. 454.Compounds were dissolved or suspended in a 2% aqueous starch suspensioncontaining 5% polyethylene glycol 400 and a drop of polysorbate 80, andadministered in a constant volume of 5 ml/kg. The results ofrepresentative compounds of this invention appear in Table IV.

                  TABLE IV                                                        ______________________________________                                        Effect on Ability of Rats to Remain                                           on an Inclined Screen                                                                                ED.sub.50                                              Compound               (mg/kg)                                                ______________________________________                                         .sub.--N--[3-(3-cyanopyrazolo[1,5- -a]pyrimidin-                                                    4.6                                                    7-yl)phenyl]- .sub.--N--ethylpropanamide                                       .sub.--N--[3-(3-cyanopyrazolo[1,5- -a]pyrimidin-                                                    3.9                                                    7-yl)phenyl]- .sub.--N--ethylacetamide                                        ______________________________________                                    

The second test to illustrate that the novel compounds of the presentinvention possess skeletal muscle relaxant properties shows the effectof representative compounds on the locomotor activity in rats. Groups of6 rats were treated orally with vehicle (5 ml/kg) or graded doses of thetest compounds. Sixty minutes later, individual rats were placed inActophotometers and locomotor activity was measured for 5 minutes aftera brief (30 sec.) habituation period. Motor activity counts (number ofcrossings of the photo cells) were recorded for each rat, and meanactivity counts were calculated for each treatment group. The dosecausing a 50% decrease in mean activity counts compared with the vehiclegroup (MDD₅₀) was calculated from a linear regression equation. The testresults of representative compounds appear in Table V.

                  TABLE V                                                         ______________________________________                                        Effects on Locomotor Activity in Rats                                                                MDD.sub.50                                             Compound               (mg/kg P.O.)                                           ______________________________________                                         .sub.--N--[3-(3-cyanopyrazolo[1,5- -a]pyrimidin-7-                                                  2.0                                                    yl)phenyl]- .sub.--N--ethylpropanamide                                         .sub.--N--[3-(3-cyanopyrazolo[1,5- -a]pyrimidin-7-                                                  1.4                                                    yl)phenyl]- .sub.--N--ethylacetamide                                          ______________________________________                                    

The novel compounds of the present invention have been found to behighly useful for drug therapy in mammals when administered in amountsranging from about 0.1 mg to about 20.0 mg/kg of body weight per day. Apreferred dosage regimen for optimum results would be from about 0.5 mgto about 10.0 mg/kg of body weight per day. Dosage units are employedsuch that a total of from about 10 to about 700 mg of active compoundfor a subject of about 70 kg of body weight are administered in a 24hour period. This dosage regimen may be adjusted to provide the optimumtherapeutic response. For example, several divided doses may beadministered daily or the dose may be proportionally reduced asindicated by the exigencies of the therapeutic situation. The compoundsof this invention are preferably administered orally but may beadministered in any convenient manner such as by the intravenous,intramuscular, or subcutaneous routes.

Compositions according to the present invention having the desiredclarity, stability and adaptability for parenteral use are obtained bydissolving from 0.10% to 10.0% by weight of active compound in a vehicleconsisting of a polyhydric aliphatic alcohol or mixtures thereof.Especially satisfactory are glycerin, propylene glycol, and polyethyleneglycols. The polyethylene glycols consist of a mixture of nonvolatile,normally liquid, polyethylene glycols which are soluble in both waterand organic liquids and which have molecular weights of from about 200to 1500. Although the amount of active compound dissolved in the abovevehicle may vary from 0.10% to 10.0% by weight, it is preferred that theamount of active compound employed be from about 3.0% to about 9.0% byweight. Although various mixtures of the aforementioned nonvolatilepolyethylene glycols may be employed, it is preferred to use a mixturehaving an average molecular weight of from about 200 to about 400.

In addition to the active compound, the parenteral solutions may alsocontain various preservatives which may be used to prevent bacterial andfungal contamination. The preservatives which may be used for thesepurposes are, for example, myristyl-gamma-picolinium chloride,benzalkonium chloride, phenethyl alcohol, p-chlorophenyl-alpha-glycerolether, methyl and propyl parabens, and thimerosal. As a practicalmatter, it is also convenient to employ antioxidants. Suitableantioxidants include, for example, sodium bisulfite, sodiummetabisulfite, and sodium formaldehyde sulfoxylate. Generally, fromabout 0.05% to about 0.2% concentrations of antioxidant are employed.

For intramuscular injection, the preferred concentration of activecompound is 0.25 to 0.50 mg/ml of the final compositions. The novelcompounds of the present invention are equally adapted to intravenousadministration when diluted with water or diluents employed inintravenous therapy such as isotonic glucose in appropriate quantities.For intravenous use, initial concentrations down to about 0.05 to 0.25mg/ml of active ingredient are satisfactory.

The active compounds of the present invention may be orallyadministered, for example, with an inert diluent or with an assimilableedible carrier, or they may be enclosed in hard or soft shell gelatincapsules, or compressed into tablets, or incorporated directly into thefood of the diet. For oral therapeutic administration, the activecompounds may be incorporated with excipients and used in the form oftablets, troches, capsules, elixirs, suspensions, syrups, wafers and thelike. Additionally, the active ingredient may be incorporated with theproper pharmaceutical carrier or carriers known in the art to produce asustained-release tablet or capsule. Such compositions and preparationsshould contain at least 0.1% of active compound. The percentage of thecompositions and preparations may, of course, be varied and mayconveniently be between about 2% to about 60% of the weight of the unitdose. The amount of active compound in such therapeutically usefulcompositions is such that a suitable dosage will be obtained.

The tablets, troches, pills, capsules and the like may also contain oneor more of the following: a binder such as gum tragacanth, acacia, cornstarch or gelatin; excipients such as dicalcium phosphate; adisintegrating agent such as corn starch, potato starch, alginic acidand the like; a lubricant such as magnesium stearate; a wetting agentsuch as sodium lauryl sulfate and a sweetening agent such as sucrose,lactose or saccharin may be added or a flavoring agent such aspeppermint, oil of wintergreen or cherry flavoring. When the dosage unitform is a capsule, it may contain, in addition to materials of the abovetype, a liquid carrier such as a fatty oil. Various other materials maybe present as coatings or to otherwise modify the physical form of thedosage unit. For instance, tablets, pills or capsules may be coated withshellac, sugar or both. A syrup or elixir may contain the activecompound, sucrose as a sweetening agent, methyl and propylparabens aspreservatives, a dye and flavoring such as cherry or orange flavor. Ofcourse, any material used in preparing any dosage unit form should bepharmaceutically pure and substantially nontoxic in the amountsemployed.

The following non-limiting examples illustrate the preparation ofrepresentative compounds of the present invention.

EXAMPLE 1 N-[3-[3-(Dimethylamino)-1-oxo-2-propenyl]phenyl]propanamide

A 20 g portion of N-(3-acetylphenyl)propanamide in 50 ml ofdimethylformamide dimethylacetal was refluxed for 8 hours, thenevaporated. The residue was taken up in 200 ml of dichloromethane,passed through hydrous magnesium silicate, diluted with hexane andconcentrated, giving 21.17 g of the desired compound.

Following the procedure of Example 1 and using the indicated startingmaterials, the amides of Examples 2-5, found in Table VI, were prepared.

                  TABLE VI                                                        ______________________________________                                        Ex.  Starting Material Amide                                                  ______________________________________                                        2     .sub.--N--(3-acetylphenyl)-                                                                     .sub.--N--[3-(3-dimethylamino)-1-                          ethanamide        oxo-2-propenyl)phenyl]-                                                       acetamide                                              3    (3-acetylphenyl)carbamic                                                                        [3-[3-dimethylamino)-1-                                     acid, methyl ester                                                                              oxo-2-propenyl]phenyl]-                                                       carbamic acid, methyl ester                            4    (3-acetylphenyl)carbamic                                                                        [3-[3-(dimethylamino)-1-                                    acid, butyl ester oxo-2-propenyl]phenyl]-                                                       carbamic acid, butyl ester                             5     .sub.--N--(3-acetylphenyl)-                                                                     .sub.--N--[3-[3-(dimethylamino)-1-                         butanamide        oxo-2-propenyl]phenyl]-                                                       butanamide                                             ______________________________________                                    

EXAMPLE 6N-[3-[3-(Dimethylamino)-1-oxo-2-propenyl]phenyl-N-ethylpropanamide

A mixture of 3.47 g ofN-[3-[3-(dimethylamino)-oxo-2-propenyl]phenyl]propanamide and 0.68 g of60% sodium hydride in oil in dimethylformamide was stirred for 0.5 hourunder argon, then cooled in an ice bath and a solution of 2.4 g of ethyliodide in 10 ml of dimethylformamide was added in small portions. Themixture was then stirred at room temperature for 0.5 hour and extractedthree times with hexane. The extracts were discarded, water was addedand this mixture extracted with dichloromethane. This extract wasevaporated and the residue crystallized from hexane giving the desiredcompound, mp 105°-107° C.

Following the procedure of Example 6 using the compounds of Examples 1-5and appropriate alkyl halides, the alkylated amides of Examples 7-12,found in Table VII, were prepared.

                  TABLE VII                                                       ______________________________________                                             Starting                                                                      Material                                                                 Ex.  of Ex.   Alkylated Amide       MP °C.                             ______________________________________                                        7    2         .sub.--N--[3-[3-(dimethylamino)-1-oxo-2-                                                           110-113                                                 propenyl]phenyl]- .sub.--N--ethylacetamide                      8    1         .sub.--N--[3-[3-(dimethylamino)-1-oxo-2-                                                           148-149                                                 propenyl]phenyl]- .sub.--N--methylpropan-                                     amide                                                           9    2         .sub.--N--[3-[3-(dimethylamino)-1-oxo-2-                                                           110-112                                                 propenyl]phenyl]- .sub.--N--propyl-                                           acetamide                                                       10   3        [3-[3-(dimethylamino)-1-oxo-2-pro-                                                                  93-95                                                   penyl]phenyl]methylcarbamic acid,                                             methyl ester                                                    11   3        [3-[3-(dimethylamino)-1-oxo-2-pro-                                                                  95-97                                                   penyl]phenyl]ethylcarbamic acid,                                              methyl ester                                                    12   2         .sub.--N--[3-[3-(dimethylamino)-1-oxo-2-                                                           146-148                                                 propenyl]phenyl]- .sub.--N--                                                  methylacetamide                                                 ______________________________________                                    

EXAMPLE 13N-[3-(3-Cyanopyrazolo[1,5-a]pyrimidin-7-yl)phenyl]-N-ethylpropanamide

A mixture of 0.54 g of 3-amino-4-pyrazolecarbonitrile and 1.37 g ofN-[3-[3-(dimethylamino)-1-oxo-2-propenyl]phenyl]-N-ethylpropanamide in50 ml of glacial acetic acid was refluxed for 8 hours and then thesolvent was removed. The residue was partitioned between saturatedaqueous sodium bicarbonate and dichloromethane. The organic layer wasseparated, dried, passed through a pad of hydrous magnesium silicate andhexane was added to the refluxing filtrate. The mixture was then cooledand the solid collected, giving 1.3 g of the desired product, mp161°-162° C.

Following the procedure of Example 13 and using appropriatelysubstituted 3-amino-pyrazoles together with the indicated intermediates,the products of Examples 14-37 found in Table VIII were prepared.

                                      TABLE VIII                                  __________________________________________________________________________       Intermediate                                                                         3-Amino-                                                            Ex.                                                                              of Ex. pyrazole Product              MP °C.                         __________________________________________________________________________    14 7      3-aminopyrazole-                                                                        .sub.--N--[3-(3-cyanopyrazolo[1,5- -a]pyrimidin-                                                  186-187                                         4-carbonitrile                                                                         7-yl)phenyl]- .sub.--N--ethylacetamide                     15 7      3-aminopyrazole                                                                         .sub.--N--ethyl- .sub.--N--(3-pyrazolo[1,5- -a]pyrimid                       in-                  115-117                                                  7-ylphenyl)acetamide                                       16 9      3-aminopyrazole                                                                         .sub.--N--propyl- .sub.--N--(3-pyrazolo[1,5- -a]pyrimi                       din-                 90-92                                                    7-ylphenyl)acetamide                                       17 9      3-aminopyrazole-                                                                        .sub.--N--[3-(3-cyanopyrazolo[1,5- -a]pyrimidin-                                                  151-153                                         4-carbonitrile                                                                         7-yl)phenyl]- .sub.--N--propylacetamide                    18 6      ethyl-3-amino-                                                                         7-[3-[ethyl(1-oxopropyl)amino]phenyl]pyra-                                                         124-126                                         pyrazole-4-                                                                            zolo[1,5- -a]pyrimidine-3-carboxylic                                 carboxylate                                                                            acid, ethyl ester                                          19 10     3-aminopyrazole-                                                                       [3-(3-cyanopyrazolo[1,5- -a]pyrimidin-                                                             168-170                                         4-carbonitrile                                                                         7-yl)phenyl]methylcarbamic acid,                                              methyl ester                                               20 10     ethyl-3-amino-                                                                         7-[3-[ (methoxycarbonyl)methyl-                                                                    115-116                                         pyrazole-4-                                                                            amino]phenyl]pyrazolo[1,5- -a]pyrimidine-                            carboxylate                                                                            3-carboxylic acid, ethyl ester                             21 3      3-aminopyrazole-                                                                       [3-(3-cyanopyrazolo[1,5- -a]pyrimidin-                                                             256-258                                         4-carbonitrile                                                                         7-yl)phenyl]carbamic acid,                                                    methyl ester                                               22 4      3-aminopyrazole-                                                                       [3-(3-cyanopyrazolo[1,5- -a]pyrimidin-                                                             131-133                                         4-carbonitrile                                                                         7-yl)phenyl]carbamic acid,                                                    butyl ester                                                23 1      3-aminopyrazole                                                                         .sub.--N--[3-(pyrazolo[1,5- -a]pyrimidin-                                                         177-178                                                  7-yl)phenyl]propanamide                                    24 1      3-aminopyrazole-                                                                        .sub.--N--[3-(3-cyanopyrazolo[1,5- -a]pyrimidin-                                                  202-204                                         4-carbonitrile                                                                         7-yl)phenyl]propanamide                                    25 1      3-amino-5-meth-                                                                         .sub.--N--[3-(3-cyano-2-methylpyrazolo[1,5- -a]-                                                  177-178                                         ylpyrazole-4-                                                                          pyrimidin-7-yl)phenyl]propanamide                                    carbonitrile                                                        26 8      3-aminopyrazole-                                                                        .sub.--N--[3-(3-cyanopyrazolo[1,5- -a]pyrimidin-                    4-carbonitrile                                                                         7-yl)phenyl]- .sub.--N--methylpropanamide                  27 8      3-amino-5-meth-                                                                         .sub.--N--[3-(3-cyano-2-methylpyrazolo[1,5- -a]-                                                  184-186                                         ylpyrazole-4-                                                                          pyrimidin-7-yl)phenyl]- .sub.-- N--methyl-                           carbonitrile                                                                           propanamide                                                28 5      3-aminopyrazole-                                                                        .sub.--N--[3-(3-cyanopyrazolo[1,5- -a]pyrimidin-                                                  138-140                                         4-carbonitrile                                                                         7-yl)phenyl]butanamide                                     29 12     3-aminopyrazole-                                                                        .sub.--N--[3-(3-cyanopyrazolo[1,5- -a]pyrimidin-                                                  195-197                                         4-carbonitrile                                                                         7-yl)phenyl]- .sub.--N--methylacetamide                    30 2      3-aminopyrazole-                                                                        .sub.--N--[3-(3-cyanopyrazolo[1,5- -a]pyrimidine-                                                 257-259                                         4-carbonitrile                                                                         7-yl)phenyl]acetamide                                      31 12     3-aminopyrazole                                                                         .sub.--N--methyl- .sub.--N--(3-pyrazolo[1,5- -a]pyrimi                       dine-                118-120                                                  7-ylphenyl)acetamide                                       32 12     ethyl-3-amino-                                                                         7-[3-(acetylmethylamino)phenyl]pyrazolo-                                                           155-156                                         pyrazole-4-                                                                            [1,5- -a]pyrimidine-3-carboxylic acid,                               carboxylate                                                                            ethyl ester                                                33 7      3-amino-4-carbo-                                                                       7-[3-(acetylethylamino)phenyl]pyrazolo-                                                            147-148                                         ethoxypyrazole                                                                         [1,5- -a]pyrimidine-3-carboxylic acid,                                        ethyl ester                                                34 2      3-amino-4-carbo-                                                                       7-[3-(acetylamino)phenyl]pyrazolo[1,5- -a]-                                                        202-204                                         ethoxypyrazole                                                                         pyrimidine-3-carboxylic acid,                                                 ethyl ester                                                35 3      3-amino-4-carbo-                                                                       7-[3-[(methoxycarbonyl)amino]phenyl]-                                                              187-188                                         ethoxypyrazole                                                                         pyrazolo[1,5- -a]pyrimidine-3-carboxylic                                      acid, ethyl ester                                          36 10     3-aminopyrazole                                                                        methyl(3-pyrazolo[1,5- -a]pyrimidin-7-                                                             107-109                                                  ylphenyl)carbamic acid, methyl ester                       37 9      3-amino-4-carbo-                                                                       7-[3-(acetylpropylamino)phenyl]pyrazolo-                                                           156-157                                         ethoxypyrazole                                                                         [1,5- -a]pyrimidine-3-carboxylic                                              acid, ethyl ester                                          __________________________________________________________________________

EXAMPLE 38N-[3-(3-Chloropyrazolo[1,5-a]pyrimidin-7-yl)phenyl]-N-ethylacetamide

A mixture of 1.0 g ofN-ethyl-N-(3-pyrazolo[1,5-a]pyrimidin-7-ylphenyl)acetamide and 4.57 g of1-chlorobenzotriazole in 50 ml of dichloromethane was refluxed for 25minutes, then cooled and poured into 50 ml of ice-cold 2.5N aqueoussodium hydroxide. The mixture was filtered through hydrous magnesiumsilicate, precipitated with hexane and the solid collected, giving 0.7 gof the desired product, mp 157°-159°C.

EXAMPLE 397-[3-[Ethyl(methoxycarbonyl)amino]phenyl]pyrazolo[1,5-a]pyrimidine-3-carboxylicacid, ethyl ester

A 12.41 g portion of[3-[3-(dimethylamino)-1-oxo-2-propenyl]phenyl]carbamic acid, methylester was reacted as described in Example 6, using 9.36 g ofethyliodide, giving 13.4 g of[3-[3-(dimethylamino)-1-oxo-2-propenyl]phenyl]ethylcarbamic acid, methylester, mp 95°-97° C.

A 2.76 g portion of the above ester was reacted with 1.55 g ofethyl-3-aminopyrazole-4-carboxylate as described in Example 13, giving2.87 g of the desired product, mp 117°-119 C.

EXAMPLE 40 [3-(3-Cyanopyrazolo[1,5-a]pyrimidin-7-yl)phenyl]ethylcarbamicacid, methyl ester

A 2.76 g portion of[3-[3-(dimethylamino)-1-oxo-2-propenyl]phenyl]ethylcarbamic acid, methylester was reacted with 1.08 g of 3-aminopyrazole-4-carbonitrile asdescribed in Example 13, giving 2.6 g of the desired product, mp162°-164° C.

EXAMPLE 41[3-(3-Cyanopyrazolo[1,5-a]pyrimidin-7-yl)phenyl]methylcarbamic acid,ethyl ester

1-Acetylphenyl-3-carbamic acid, ethyl ester was converted to[3-[3-(dimethylamino)-1-oxo-2-propenyl]phenyl]carbamic acid, ethyl esterby the procedure of Example 1 and this ester was then reacted withmethyl iodide, again by the procedure of Example 6, giving[3-[3-(dimethylamino)-1-oxo-2-propenyl]phenyl]methylcarbamic acid, ethylester.

A 2.6 g portion of the above ester was reacted with 1.08 g of3-aminopyrazole-4-carbonitrile by the procedure of Example 13, giving2.09 g of the desired compound, mp 140°-142° C.

EXAMPLE 42 Ethyl(3-pyrazolo[1,5-a]pyrimidin-7-ylphenyl)carbamic acid,ethyl ester

[3-[3-(Dimethylamino)-1-oxo-2-propenyl]phenyl]carbamic acid was reatedwith ethyl iodide by the procedure of Example 6, giving[3-[3-(dimethylamino)-1-oxo-2-propenyl]phenyl]ethylcarbamic acid, ethylester.

A 2.9 g portion of the above ester was reacted with 0.83 g of3-aminopyrazole by the procedure of Example 13, giving 2.27 g of thedesired product, mp 79°-81° C.

EXAMPLE 43 [3-(3-Cyanopyrazolo[1,5-a]pyrimidin-7-yl)phenyl]ethylcarbamicacid, ethyl ester

A 2.0 g portion of[3-[3-(dimethylamino)-1-oxo-2-propenyl]phenyl]ethylcarbamic acid, ethylester was reacted with 1.08 g of 3-aminopyrazole-4-carbonitrile asdescribed in Example 13, giving 2.52 g of the desired product, mp133°-135° C.

EXAMPLE 44[3-(3-Chloropyrazolo[1,5-a]pyrimidin-7-yl)phenyl]ethylcarbamic acid,ethyl ester

A 1.55 g portion ofethyl(3-pyrazolo[1,5-a]-pyrimidin-7-ylphenyl)carbamic acid, ethyl esterin 50 ml of dichloromethane was reacted with 1-chlorobenzotriazole for30 minutes, giving 1.29 g of the desired product, mp 100°-102° C.

EXAMPLE 45N-[3-(3-Cyanopyrazolo[1,5-a]pyrimidin-7-yl)phenyl]-N-2-propenylacetamide

An 11.61 g portion ofN-[3-[3-(dimethylamino)-1-oxo-2-propenyl]phenyl]acetamide was reactedwith 7.26 g of allyl bromide as described in Example 6, giving 13.34 gofN-[3-[3-(dimethylamino)-1-oxo-2-propenyl]phenyl]-N-2-propenylacetamide,mp 91°-94° C.

A 1.36 g portion of the above intermediate was reacted with 0.54 g of3-aminopyrazole-4-carbonitrile as described in Example 13, giving 1.0 gof the desired compound, mp 135°-137° C.

EXAMPLE 46N-[3-(3-Cyanopyrazolo[1,5-a]pyrimidin-7-yl)phenyl]-N-2-propynylacetamide

An 11.61 g portion ofN-[3-[3-(dimethylamino)-1-oxo-2-propenyl]phenyl]acetamide was reactedwith propynyl bromide as described in Example 6, givingN-[3-[3-(dimethylamino)-1-oxo-2-propenyl]phenyl]-N-2-propynylacetamide,mp 98°-101° C.

A 2.7 g portion of the above intermediate was reacted with 1.08 g of3-aminopyrazole-4-carbonitrile as described in Example 13, giving 1.90 gof the desired product, mp 193°-195° C.

EXAMPLE 47N-Butyl-N-[3-(3-cyanopyrazolo[1,5-a]pyrimidin-7-yl)phenyl]acetamide

An 11.61 g portion of[3-[3-(dimethylamino)-1-oxo-2-propenyl]phenyl]carbamic acid, methylester was reacted with 11.0 g of butyl iodide by the procedure ofExample 6, giving 16.3 g ofN-butyl-N-[3-[3-(dimethylamino)-1-oxo-2-propenyl]phenyl]acetamide.

A 2.88 g portion of the above intermediate was reacted with 1.08 g of3-aminopyrazole-4-carbonitrile by the procedure of Example 13, giving1.61 g of the desired product, mp 146°-148° C.

EXAMPLE 48N-[3-(3-Cyanopyrazolo[1,5-a]pyrimidin-7-yl)phenyl]-N-methylcarbamicacid, butyl ester

An 11.61 g portion of [3-[3-(dimethylamino)-1-oxo-2-propenyl]phenyl]carbamic acid, butyl ester was reacted with 6.82 g ofmethyl iodide by the procedure of Example 6, giving 11.67 g of[3-[3-(dimethylamino)-1-oxo-2-propenyl]phenyl]methylcarbamic acid, butylester.

A 3.04 g portion of the above ester was reacted with 1.08 g of3-aminopyrazole-4-carbontirile as described in Example 13, giving 2.3 gof the desired product, mp 96°-97° C.

EXAMPLE 49N-[3-(3-Chloropyrazolo[1,5-a]pyrimidin-7-yl)phenyl]-N-methylacetamide

A 1.0 g portion ofN-methyl-N-(3-pyrazolo[1,5-a]pyrimidin-7-ylphenyl)acetamide was reactedas described in Example 38, giving 1.0 g of the desired product, mp163°-165° C.

EXAMPLE 50[3-(3-Chloropyrazolo1,5-a]pyrimidin-7-yl)phenyl]methylcarbamic acid,methyl ester

A 1.4 g portion of methyl(3-pyrazolo[1,5-a]pyrimidin-7-ylphenyl)carbamicacid, methyl ester was reacted as described in Example 38, giving 1.42 gof the desired product, mp 132°-134° C.

EXAMPLE 517-[3-[(Cyclopropylcarbonyl)methylamino]phenylpyrazolo[1,5-a]pyrimidine-3-carboxylicacid, ethyl ester

N-(3-Acetylphenyl)cyclopropanecarboxamide was prepared by the reactionof m-aminoacetophenone, diisopropylethylamine and cyclopropanecarboxylicacid chloride in dichloromethane.

This compound was then converted toN-[3-[3-(dimethylamino)-1-oxo-2-propenyl]phenyl]cyclopropanecarboxamideby the procedure of Example 1 and then alkylated by the procedure ofExample 6, using methyl iodide, giving 10.17 g ofN-[3-(3-dimethylamino)-1-oxo-2-propenyl)phenyl]-N-methylcyclopropanecarboxamide,mp 120°-122° C.

A 0.54 g portion of this compound was reacted as described in Example 13with 3-aminopyrazole-4-carbonitrile, giving 1.08 g of the desiredproduct, mp 178°-180° C.

EXAMPLE 527-[3-[(Cyclopropylcarbonyl)methylamino]phenylpyrazolo[1,5-a]pyrimidine-3-carboxylicacid, ethyl ester

A 0.73 g portion of ethyl 3-aminopyrazole-4-carboxylate and 1.36 g ofN-[3-[(3-(dimethylamino)-1-oxo-2-propenyl]phenyl]-N-methylcyclopropanecarboxamidewere reacted as described in Example 13, giving 0.52 g of the desiredproduct, mp 122°-124° C.

EXAMPLE 53N-[3-(3-Cyanopyrazolo[1,5-a]pyrimidin-7-yl)phenyl]-N-methylcyclobutanecarboxamide

m-Aminoacetophenone, cyclobutanecarboxylic acid, chloride anddiisopropylethylamine in dichloromethane were reacted, givingN-(3-acetylphenyl)cyclobutanecarboxamide.

This compound was then converted toN-[3-[3-(dimethylamino)-1-oxo-2-propenyl]phenyl]cyclobutanecarboxamide,mp 155°-157° C., by the procedure of Example 1 and further alkylated bythe procedure of Example 6, using methyl iodide to give 8.32 g ofN-[3-[3-(dimethylamino)1-oxo-2-propenyl]phenyl]-N-methylcyclobutanecarboxamide,mp 117°-119° C.

A 0.54 g portion of 3-aminopyrazole-4-carbonitrile was reacted with 1.43g of the above product by the procedure of Example 13, giving 1.3 g ofthe desired product, mp 157°-158° C.

EXAMPLE 547-[3-[(Cyclobutylcarbonyl)amino]phenyl]pyrazolo[1,5-a]pyrimidine-3-carboxylicacid, ethyl ester

A 0.78 g portion of 3-amino-4-carboethoxypyrazole ard 1.36 g ofN-[3-[3-(dimethylamino)-1-oxo-2-propenyl]phenyl]cyclobutanecarboxamidewere reacted as described in Example 13, giving 1.52 g of the desiredproduct, mp 123°-125° C.

What is claimed is:
 1. A compound of the formula: ##STR7## wherein R₁ isselected from the group consisting of hydrogen, halogen, cyano and##STR8## R₂ is selected from the group consisting of hydrogen and alkyl(C₁ -C₃); R₃ is ##STR9## R₄ is selected from the group consisting ofhydrogen, alkyl(C₁ -C₆) and alkoxy(C₁ -C₆); R₅ is selected from thegroup consisting of hydrogen, alkyl(C₁ -C₆), alkenyl(C₂ -C₆), --CH₂C.tbd.CH, cycloalkyl(C₃ -C₆)methyl, --CH₂ OCH₃ and --CH₂ CH₂ OCH_(3;)and R₆ is selected from the group consisting of alkyl(C₁ -C₆),cycloalkyl(C₃ -C₆), --O-alkyl(C₁ -C₆), --NH-alkyl(C₁ -C₃),--N-dialkyl(C₁ -C₃), --(CH₂)_(n) --O-alkyl(C₁ -C₃), --(CH₂)_(n)--NH-alkyl(C₁ -C₃) and --(CH₂)_(n) --N-dialkyl(C₁ -C₃), where n is aninteger 1 to 3 inclusive.
 2. A compound according to claim 1, wherein R₁is cyano or ##STR10## R₂ is hydrogen; R₄ is alkyl(C₁ -C₆),alkenyl(C_(2-C) ₆) or --CH₂ .tbd.CH; and R₆ is alkyl (C₁ -C₆),cycloalkyl(C₃ -C₆) or --O-alkyl(C₁ -C₆).
 3. The compound according toclaim 2, which isN-[3-(3-cyanopyrazolo[1,5-a]pyrimidin-7-yl)phenyl]-N-ethylpropanamide.4. The compound according to claim 2, which isN-[3-(3-cyanopyrazolo[1,5-a]pyrimidin-7-yl)phenyl]-N-ethylacetamide. 5.The compound according to claim 2, which isN-[3-(3-cyanopyrazolo[1,5-a]pyrimidin-7-yl)phenyl]-N-propylacetamide. 6.The compound according to claim 2, which is[3-(3-cyanopyrazolo[1,5-a]pyrimidin-7-yl)phenyl]methylcarbamic acid,methyl ester.
 7. The compound according to claim 2, which is7-[3-[(methoxycarbonyl)methylamino]phenyl]pyrazolo[1,5-a]pyrimidine-3-carboxylicacid, ethyl ester.
 8. The compound according to claim 2, which is[3-(3-cyanopyrazolo[1,5-a]pyrimidin-7-yl)phenyl]ethylcarbamic acid,methyl ester.
 9. The compound according to claim 2, which isethyl(3-pyrazolo[1,5-a]pyrimidin-7-ylphenyl)carbamic acid, ethyl ester.10. The compound according to claim 2, which is[3-(3-chloropyrazolo[1,5-a]pyrimidin-7-yl)phenyl]ethylcarbamic acid,ethyl ester.
 11. The compound according to claim 2, which isN-[3-(3-cyanopyrazolo[1,5-a]pyrimidin-7-yl)phenyl]-N-2-propenylacetamide.12. The compound according to claim 2, which isN-[3-(3-cyanopyrazolo[1,5-a]pyrimidin-7-yl)phenyl]-N-2-propynylacetamide.13. The compound according to claim 2, which isN-[3-(3-cyanopyrazolo[1,5-a]pyrimidin-7-yl)phenyl]-N-methylacetamide.14. A method of ameliorating anxiety in a mammal which comprisesadministering to said mammal an amount of a compound of claim 1sufficient to reduce anxiety.
 15. A composition of matter in dosage unitform comprising from 2-750 mg of a compound of claim 1 in associationwith a pharmaceutically acceptable carrier.